权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Immunoregulatory Mechanisms of IL-33 in Heart Transplantation

IL-33在心脏移植中的免疫调节机制

基本信息

批准号：
10680570
负责人：
Heth R Turnquist
金额：
$ 61.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680570
关键词：
Alloantigen Allogenic Allografting Antigens Arteries B-Lymphocytes Blood Vessels Brain Death Cause of Death Cell Communication Cells Cessation of life Childhood Chronic Cicatrix Clinical Communication Data Development Disease Resistance Dissection Event Fibroblasts Fibrosis Generations Graft Rejection Growth Factor Heart Transplantation Immune Immune response Immune system Immunoglobulins Immunologics Immunosuppressive Agents Infiltration Inflammation Inflammatory Inflammatory Response Injury Innate Immune System Interferon Type II Interleukin-13 Interleukins Ischemia Life Macrophage Mediating Memory Metabolism Modeling Molecular Mus Myeloid Cells Operative Surgical Procedures Organ Transplantation Pathologic Pathway interactions Pattern Process Production Proliferating Publishing Regulatory T-Lymphocyte Reperfusion Injury Research Resolution Rodent Sampling Secondary to Signal Transduction Stress Stromal Cells T-Cell Proliferation T-Lymphocyte Technology Testing Tissues Transgenic Mice Transplant Recipients Transplantation Trauma Vascular Diseases arginase chemokine cytokine cytotoxicity directed differentiation immunoregulation improved outcome insight isoimmunity monocyte post-transplant pre-clinical prevent promoter receptor repaired response response to injury tissue repair transcriptomics transplant model

项目摘要

Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death, ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro- inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33 mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells (Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production in the graft. We have established that monocytes and macrophages recognize and develop allospecific cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate alloimmunity prevents effective injury resolution and repair after heart transplantation.

早期移植物损伤是不可避免的移植相关事件的结果，例如供体脑死亡，缺血/再灌注损伤和手术创伤。对移植物同种抗原的免疫应答也会产生移植物在移植物的整个生命周期内都有损伤。这些伤害和压力导致自我分子的释放包含损伤相关分子模式（DAMP）。值得赞赏的是，DAMP支持亲- 当它们被先天免疫系统的细胞，特别是单核细胞感知时，和巨噬细胞。临床前啮齿动物心脏移植研究表明，这些释放的DAMP启动和传播同种异体反应和靶向炎性DAMP，或它们激活的信号级联，同种异体免疫和改善移植后的结果。然而，我们最近的研究提供了令人信服的结果有证据表明，这些移植物损伤也释放修复性DAMP（rDAMP），如白细胞介素-33（IL-33），限制局部炎症并启动心脏移植后免疫介导的组织修复。通过评估儿科心脏移植受者样本，并使用临床前小鼠心脏移植模型，我们发现， IL-33在移植物基质细胞中上调，限制了同种异体移植物血管病变和移植物纤维化，后来在慢性排斥反应（CR）中达到高潮。我们发表的和初步的数据表明，IL-33 通过靶向浸润的单核细胞和巨噬细胞以及调节性T细胞介导这种保护作用（TcB），以限制促炎性巨噬细胞的产生，然后协调Treg和修复性巨噬细胞。巨噬细胞介导的损伤反应。虽然这些数据令人鼓舞，但我们的研究也表明，启动早期组织损伤修复的过程可能在移植物的寿命中变得失调。初步数据，我们表明，血管相关性T细胞炎成为病理性时，他们的持续分泌修复因子响应于IL-33，促进了有助于CR的局部成纤维细胞的增殖。除了拥有他们的由局部rDAMP编程的功能，移植物浸润受体单核细胞识别同种异体分子使它们成熟为促炎性骨髓细胞，刺激T细胞增殖和IFNγ产生在移植物中。我们已经确定单核细胞和巨噬细胞识别和发展同种异体特异性通过成对的免疫球蛋白样受体-A对MHCI抗原的细胞毒性和记忆。这些数据使我们假设rDAMP信号启动心脏移植后早期组织损伤修复由于同种异体反应性免疫引起的持续炎症反应，细胞我们将在两个目标中测试这一假设：在AIM 1中，我们将定义rDAMP和免疫细胞的相互作用在CR发展过程中，心脏移植微环境会发生变化。在AIM 2中，我们将确定同种免疫阻止心脏移植后有效的损伤解决和修复。